Natural killer (NK) cells are able to recognize and kill aberrant (i.e., cancerous and virus-infected) cells without priming and independently of the antigenic presentation/composition of the target. NK cells have been shown to protect against development of cancer. Accordingly, identification and pre-clinical/clinical development of agents that are relatively safe but can boost NK cell function are highly desirable with immense translational application for chemoprevention of cancers. This project seeks to test a novel hypothesis that prostate cancer prevention by benzyl isothiocyanate (BITC), a constituent of many edible cruciferous vegetables, is at least in part mediated by augmentation of NK cell function. This hypothesis stems from our novel preliminary unpublished results showing BITC-mediated augmentation of NK cell lytic activity in vitro at pharmacologically relevant concentrations. In addition, the BITC-mediated augmentation of NK cell lytic activity correlates with increased production of interferon gamma (IFN3) and tumor necrosis factor-alpha (TNF1) by the NK cells. Despite these encouraging results, the in vivo significance of these in vitro observations is unclear. Likewise, the mechanism by which BITC augments NK cell activity remains elusive. The overall objective of this application is to systematically probe into these questions using prostate cancer as a disease model. The rationale for focusing on prostate cancer is based on the following considerations: (a) epidemiological studies have indicated an inverse correlation between dietary intake of cruciferous vegetables and the risk of prostate cancer, and (b) a very recent study has provided important genetic evidence for surveillance of primary tumors by NK cells in the TRAMP model of prostate cancer. The specific aims of this proposal are to (1) determine the concentration effect relationship for dietary BITC administration on tumoricidal activity of NK cells in vivo and to gain insight into the mechanism of this effect, and (2) determine whether dietary BITC- mediated boost of NK cell activity leads to suppression of prostate carcinogenesis and metastasis in TRAMP mice in vivo. Positive outcome of these studies will form a firm basis for clinical trials to determine BITC-mediated augmentation of NK cell activity and prostate carcinogenesis in humans. ) PUBLIC HEALTH RELEVANCE: We have found that dietary benzyl-isothiocyanate (BITC) is able to augment host NK cell function. In this project, we will investigate the in vivo aspects of BITC intake on the tumoricidal capacity of the host's NK cells. We will first determine the concentration effect relationship for dietary BITC administration on the tumoricidal activity of NK cells in vivo and we will determine the mechanism behind this effect. We will then determine whether the dietary BITC-mediated boost of NK cell activity leads to suppression of carcinogenesis and metastasis in the TRAMP model of prostate cancer.